The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.
Pubmed ID: 29336889 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
A software package to analyze next-generation resequencing data. The toolkit offers a wide variety of tools, with a primary focus on variant discovery and genotyping as well as strong emphasis on data quality assurance. Its robust architecture, powerful processing engine and high-performance computing features make it capable of taking on projects of any size. This software library makes writing efficient analysis tools using next-generation sequencing data very easy, and second it's a suite of tools for working with human medical resequencing projects such as 1000 Genomes and The Cancer Genome Atlas. These tools include things like a depth of coverage analyzers, a quality score recalibrator, a SNP/indel caller and a local realigner. (entry from Genetic Analysis Software)
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsA genomics database project is an academic research program to identify molecular features of cancers that predict response to anti-cancer drugs.
View all literature mentionsThis monoclonal targets IgG
View all literature mentionsThis unknown targets
View all literature mentionsThis polyclonal secondary targets IgG
View all literature mentionsThis monoclonal targets Braf
View all literature mentionsThis monoclonal targets c-Raf, phospho (Ser338)
View all literature mentionsThis monoclonal targets S6 Ribosomal Protein
View all literature mentionsThis monoclonal targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb
View all literature mentionsThis monoclonal targets MEK1/2 (D1A5) Rabbit mAb
View all literature mentionsThis monoclonal targets Phospho-MEK1/2 (Ser217/221)
View all literature mentionsThis monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis polyclonal targets HSP90AA1, HSP90AB1, HSP90B1
View all literature mentionsThis monoclonal targets HA-Tag
View all literature mentionsThis monoclonal targets RRAS2
View all literature mentions